Evolutionary capacitor mechanisms such as the yeast prion [PSI+] and the heat shock protein HspQO store variation in a latent form and reveal it later. Capacitors appear to be common, and could be key components of genetic architecture. Capacitors help explain why a disease allele in 1 genetic and environmental context could be harmless in a different context. Perhaps because the biology of capacitance is substantially different from the mutation, recombination, and selection processes typically studied by population genetics, capacitors remain poorly understood from a theoretical perspective. The proposed work will develop a novel population genetics theory to capture the essence of capacitor biology in a finite population undergoing rare environmental change events. The theory will focus on the invasion probabilities of alleles that modify the probability with which variation is revealed. The theory will be used to predict the circumstances under which such alleles will be favored. It will incorporate unusual aspects of capacitor biology, such as the fact that variation is revealed at multiple sites simultaneously, and that revelation is easily reversible. Another unusual aspect of capacitor biology is that hidden variation may be subject to low levels of selection rather than no selection. Mild selection in the hidden state, by removing strongly deleterious mutants, may enrich hidden variation for potentially adaptive traits. This phenomenon of preadaptation will be incorporated into the model framework and its impact on capacitor-mediated adaptation will be assessed. The theoretical framework for capacitance will be reinforced by using comparative yeast genomics of 3'untranslated regions to survey the evidence for past [PSI+] capacitance activity and for preadaptation of the variation revealed by [PSI+]. In the context of public health, the complex genetic architecture of human disease often confounds attempts at genetic analysis. A solid understanding of evolutionary capacitance may provide a new framework for such analyses in the future. Since direct experiments on capacitance cannot be performed in humans, the theoretical and predictive approach described here is particularly important for understanding the scope of capacitance in explaining human variation.